Assessment of Sleep in Children with

Mucopolysaccharidosis Type III

Louise Victoria Mahon1*, Michelle Lomax1, Sheena Grant1, Elaine Cross1, Dougal Julian Hare1, James
Ed Wraith2, Simon Jones2, Brian Bigger3, Kia Langford-Smith3, Maria Canal4
1 Division of Clinical Psychology, University of Manchester, Manchester, United Kingdom, 2 Genetic Medicine, St. Marys Hospital, Manchester, United Kingdom, 3 Faculty
of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom, 4 Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom

Abstract
Sleep disturbances are prevalent in mucopolysaccharidosis Type III (MPS III), yet there is a lack of objective, ecologically valid
evidence detailing sleep quantity, quality or circadian system. Eight children with MPS III and eight age-matched typically
developing children wore an actigraph for 710 days/nights. Saliva samples were collected at three time-points on two
separate days, to permit analysis of endogenous melatonin levels. Parents completed a sleep questionnaire and a daily sleep
diary. Actigraphic data revealed that children with MPS III had significantly longer sleep onset latencies and greater daytime
sleep compared to controls, but night-time sleep duration did not differ between groups. In the MPS III group, sleep
efficiency declined, and sleep onset latency increased, with age. Questionnaire responses showed that MPS III patients had
significantly more sleep difficulties in all domains compared to controls. Melatonin concentrations showed an alteration in
the circadian system in MPS III, which suggests that treatment for sleep problems should attempt to synchronise the sleepwake cycle to a more regular pattern. Actigraphy was tolerated by children and this monitoring device can be
recommended as a measure of treatment success in research and clinical practice.
Citation: Mahon LV, Lomax M, Grant S, Cross E, Hare DJ, et al. (2014) Assessment of Sleep in Children with Mucopolysaccharidosis Type III. PLoS ONE 9(2): e84128.
doi:10.1371/journal.pone.0084128
Editor: Stephen D. Ginsberg, Nathan Kline Institute and New York University School of Medicine, United States of America
Received August 27, 2013; Accepted November 12, 2013; Published February 4, 2014
Copyright: 2014 Mahon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The MPS Society UK (http://www.mpssociety.org.uk/) partially funded the study. No additional external funding was received for this study. The funders
had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: louise_mahon@hotmail.com

awake all night, crying out, wandering around the house at night,
getting into parents bed, laughing and singing at night [7], [8].
Colville et al. [8] reported that children with MPS IIIB showed
higher rates of early morning waking and night waking compared
to sub-type A. The average age of onset of sleep problems was 3.8
years and caregivers noted an association between night-time sleep
disturbance and daytime sleepiness or aggressive behaviours [10].
Although no medications were unanimously judged to be effective,
melatonin was viewed as the most helpful [10] and 50% of
behavioural interventions resulted in meaningful improvements
[10], [8]. Clinicians reported 8095% of MPS III patients
experienced sleep difficulties and daytime behaviours were worse
when sleep difficulties were more severe, however some reported
that behaviour actually improved when sleep was disturbed [11].
Objective measurement of sleep can be achieved by the use of
polysomnography (PSG) and actigraphy. Mariotti et al. [12]
utilised PSG with six individuals with MPS IIIA aged 720 years
(mean 14.1 years). Compared to age- and sex-matched controls,
MPS III patients displayed less nocturnal sleep (240.5 min vs.
458.3 min), REM sleep (8.03% vs. 21.53%) and slow wave sleep
(10.18% vs. 24.63%), but greater daytime sleep (88.8 min vs.
24.8 min). The youngest two patients (aged 7 & 9 years) slept
mainly at night but displayed nocturnal waking, whereas children
aged 12+ years showed very fragmented sleep of variable duration
across night and day. Actigraphy detects body movement to
distinguish between wakefulness and sleep. Actigraphy is more
precise than sleep diaries [13], correlates highly with PSG [14], is

Introduction
Mucopolysaccharidosis type III (MPS III/Sanfilippo syndrome)
is an inherited metabolic disorder characterised by an absence/
defect of lysosomal enzymes needed to break down glycosaminoglycans (GAGs). Accumulation of GAGs leads to progressive
dysfunction of cells, tissues and organs [1], [2]. Incidence varies
across countries with 1.21 per 100,000 babies affected in the UK
[1]. MPS III has three phases [3], with the first phase (14 years)
characterised by developmental delay, the second phase (410
years) by behavioural disturbance, including sleep difficulties,
aggressive or destructive behaviours, hyperactivity and attention
difficulties, and the third/end phase (10+ years) by progressive loss
of skills (especially language), seizures, and problems with mobility
and swallowing. The four sub-types of MPS III A-D correspond to
variations in enzyme deficiency, with A and B being the most
common and D the most rare. There is little clinical difference
between subtypes [3], but A might show a more severe course [4]
and C a more attenuated course [5].
Sleep difficulties are prevalent in MPS III, particularly settling
problems, night-time waking and early morning waking [6]. Both
pharmacological and behavioural approaches have been used and
although some improvement has been reported, most treatment
has been unsuccessful. To date, there are a small number of papers
on sleep in MPS III. In four studies using parental questionnaires,
between 6791.5% of MPS III patients exhibited sleep disturbance
[710], including settling difficulties, night-time waking, staying

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Sleep in MPS III

Table 1. MPS III Participant Information.

Previous treatment
for sleep problems
(effectivenessa)
None

Sex

Age

Ethnicity

MPS III subtype

Current intervention
(effectivenessa)

Male

Pakistani

None

Male

White Polish

None

None

Male

White British B

None

Behavioural advice
(parents already
used the techniques)

Male

10

Pakistani

Melatoninb (good for settling),

Loperamide

Herbal medicine
(not effective after
the first week)

Female

10

Pakistani

Walking (seems to help)

Risperidone (not very helpful)

None

Female

11

White British A

Gonapeptyl

None

Male

14

White British A

Chloral hydrate, Zopiclone

(both effective in the short-term,
not long-term), Levetiracetam,
Ibuprofen, Hyoscine

Melatonin (effective
in the short-term, not longterm), Behavioural
modification (not effective)

Female

15

White British A

Zopiclone, Clonazepam,
Midazolam, Sodium Valproate,
Senokot, Movicol, Omeprazole,
Glycopyrrolate, Morphine, Paracetamol

Melatonin (no effect),

Temazepam (effective
initially but became tearful & distressed)

Effectiveness of treatment as evaluated by parents.

Melatonin was withdrawn for the study.
doi:10.1371/journal.pone.0084128.t001
b

less expensive and less intrusive than PSG, and can be used to
gather with naturalistic sleep data over a long period.
It is proposed that there are abnormalities in the circadian
rhythm of melatonin concentration in specific developmental
disorders, for example an inversion of the circadian rhythm of
melatonin has been demonstrated in Smith-Magenis syndrome
[15], [16]. Given the presence of irregularly distributed sleep,
which appears to be dispersed over day and night in individuals
with MPS III, it has been suggested that there is an abnormality of
the circadian rhythm of melatonin in this disorder. Guerrero,
Pozo, Diaz-Rodriguez, Martinez-Cruz, and Vela-Campos [17]
compared twelve patients with MPS III and nine controls aged 6
14 years over a 24-hour period. Compared to the control group,
MPS III patients had lower levels of melatonin at night and higher
levels during the day. In a mouse model study [18], MPS IIIB
mice had higher levels of activity during the resting phase, a
reduced resting phase and lower amplitude rhythm compared to
age-matched control mice. These findings support the concept of
circadian system dysfunction in MPS III, which could in turn act
as an important biomarker and clinical outcome measure [19],
[20].
The primary aim of the present study was to gather objective,
ecologically valid information on sleep and circadian rhythms in
children with MPS III. It was hypothesised that MPS III patients
would show greater settling difficulties, reduced night-time sleep,
poorer quality sleep, increased daytime sleep and an alteration of
the circadian system, compared to controls. A secondary aim was
to determine the suitability of actigraphy with this patient group
and the potential use of actigraphy as a clinical outcome measure.
No previous investigations have used actigraphy or salivary
melatonin analyses in MPS III and none have combined sleep
questionnaires with actigraphy and melatonin testing to examine
sleep and circadian alterations in MPS III patients.

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Methods
Ethics Statement
National Research Ethics Service: North West 12 Research
Ethics Committee, Lancaster (REC reference number: 11/NW/
0068) approved the study.

Participants
Eight children with MPS III (5 males, 3 females; mean age 9
years 3 months, SD 4.86, age range 215 years) were enrolled
through their physicians at the Willink Biochemical Genetics Unit
or through the MPS Society UK. Children were selected based on
their diagnosis rather than the presence of sleep disturbance, and
diagnosis was confirmed by analysis of urine GAGs and specific
enzyme analysis. Patients who were involved in a drug study, had a
bone marrow transplant, a serious disease affecting another organ,
or were near the end of life as advised by their doctor were
excluded from this study. Demographic details are displayed in
Table 1. Two MPS III participants had epilepsy, and parents of
one of these children noted that a lack of sleep at night triggered
seizures. The younger patients were not taking any medications,
whereas the older patients were prescribed drugs for sleep (e.g.
melatonin, chloral hydrate, zopiclone), epilepsy (e.g. sodium
valproate), and other symptoms, such as pain. Only one patient
was currently prescribed melatonin, but as exogenous melatonin
impacts circadian rhythms [21], it was ceased two weeks prior to
data collection. This ensured that no lingering effects of melatonin
masked the circadian behaviour or the physiologic levels of
melatonin in saliva samples. No other medications were altered. A
group of age-matched controls (4 males, 4 females; mean age 8
years 7 months, SD 4.85, age range 315 years) were selected who
did not have a developmental disability, psychiatric disorder,
neurological disorder/brain injury or sleep disorder and none
were taking medication.

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Sleep in MPS III

Oral and written informed consent was obtained from a parent

of each child. Typically developing children aged six to thirteen
years also gave their assent (oral and written), and those aged
fourteen to fifteen years provided consent (oral and written). All
children received a gift voucher for taking part.

Analysis
Actigraphic data were transferred to Actiware version 5.5
software (Respironics). Rest intervals were set based on diary
information and review of the actogram (where activity and light
intensity decreased). Actigraphic and questionnaire data were
entered onto SPSS version 19 for analysis. One nights actigraphy
data had to be excluded from the analysis for several participants
due to illness or non-compliance, but a minimum of seven nights
data were available for all subjects. An alpha level of 0.05 was used
for all statistical tests.

Materials and Procedure

A letter outlining the project was sent to all families with a child
with MPS III who were under the care of the Willink Unit or
known to the MPS Society UK. Children of colleagues at the
University of Manchester or a local NHS Trust formed the control
group. Participant information sheets were provided to families
who expressed an interest in taking part. A researcher met with
each family and the childs demographic details were gathered.
Parents completed the Childrens Sleep Habits Rating Scale (E.
Shapiro, personal communication, September 6, 2010), a checklist
adapted from the Childrens Sleep Habits Questionnaire [22] to
assess sleep problems in patients with MPS III. The checklist
required parents to indicate how often each sleep behaviour
occurred in a typical week. Items were rated on a three-point scale:
usually for behaviours occurring five to seven times per week,
sometimes for those happening two to four times per week, and
rarely/never for behaviours shown up to once per week.
All children wore an actigraph (Respironics Actiwatch 2/
Cambridge Neurotechnology AW4) on their non-dominant wrist
for seven to ten days and nights, whilst carrying out their usual
activities. A 15 second sampling interval was employed. Previous
research found that a minimum of five nights data are needed to
provide meaningful actigraphic recordings of a childs sleep, and
actigraphic monitoring should cover at least seven nights to
compensate for factors such as illness, technical problems and noncompliance [23]. Recording for a minimum of a week meant that
data could be gathered over school days and over the weekend, as
well as allowing for potential loss of data. The sleep parameters of
interest were sleep onset latency (time between lights out and
sleep onset), total night-time sleep duration, sleep efficiency
(percentage of time asleep between time of lights out and get
up), wake after sleep onset (WASO, total number of minutes
awake between sleep onset and time of final waking), time in bed
(minutes) and total daytime sleep duration (total number of
minutes asleep between time of final waking and bed time). To
avoid confounding effects of large seasonal variation in circadian
rhythms, data was gathered within a six-month period and during
school term time to ensure comparability across subjects.
Caregivers noted their childs bed times, get up times, lights on/
off times and any night-time events in a daily diary.
To allow examination of endogenous melatonin levels, parents
took saliva samples from their child at three time points (between
68 h, 1012 h, & 2224 h), on the first and last day of
actigraphic recording. Samples were collected using a suction
catheter (de Lee suction catheter; Argyle, Sherwood Medical,
Tullamore, Ireland) and were frozen at 220uC until analysis.
Night collection was performed under dim light conditions.
Samples were collected in accordance with procedures outlined
by the enzyme-linked immunosorbent assays (ELISA) kit manufacturer (www.IBL-International.com), to allow testing using NonExtraction Melatonin Saliva ELISA (IBL, Hamburg, Germany).
Preliminary analyses indicated that the data were reliable as
standard deviations were less than 20% of the mean. One outlier
was removed. Some saliva samples were missing or incomplete
and were excluded (pairwise), but 88.5% of saliva samples were
useable.

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Results
Childrens Sleep Habits Rating Scale
The average age of onset of sleep problems for MPS III patients
was 2 years (SD 2.33, range birth-7 years). Sleep problems
identified by parents included difficulties settling, waking up
during the night, early morning wakening, and sleeping too little.
Most children (62.5%) needed a parent in the room whilst trying
to sleep. Half of the children fell asleep within twenty minutes on
some nights, but 37.5% rarely or never did. Most parents believed
their child slept too little on at least two nights each week, but on
other nights they seemed to sleep the right amount. The majority
of children woke up once (62.5%), or multiple times (87.5%) at
night. Most of the children (75%) displayed disruptive behaviour
at night (e.g. screaming, singing, laughing), and 25% of children
displayed dangerous behaviours (e.g. running outside, playing with
appliances). All children were restless and moved a lot at night and
50% of children slept during the day.
Mann Whitney U tests demonstrated that the MPS III group
had significantly more disturbed sleep in all areas assessed by the
Childrens Sleep Habits Rating Scale. Results are displayed in
Table 2.

Actigraphy
As suggested by Acebo et al. [23], actigraphic data for each
participant were averaged over the recording period prior to
analysis. Actigraphic data for each MPS III patient can be seen in
Table 3. Night-time sleep is diminished in some patients,
particularly P8 who only slept for an average of 190 minutes per
night, however most children slept a normal amount at night. Five
out of eight children slept during the day on occasions during
actigraphic monitoring, but most children did not nap every day.
Sleep onset latency was markedly high in the majority of children.
One of the youngest children settled very quickly, within
approximately 6 minutes, but the eldest two children had distinctly
long sleep onset latencies of approximately 1 hour 10 minutes and
3 hours respectively. The remaining five children took between 25
minutes and 40 minutes to enter a sleep state. Sleep efficiency was
diminished in some children, with the eldest child sleeping only
28% of the time in bed and the five year old sleeping just 59% of
the time in bed. WASO was elevated in all children, notably the
oldest two subjects, and it ranged from 64 minutes to 207 minutes
per night across participants.
Actigraphic data from the groups were analysed using MannWhitney U tests and results are displayed in Table 4. Sleep onset
latency was significantly longer in children with MPS III
compared to the control group. Night-time sleep duration and
time in bed did not differ significantly between the groups. WASO
was higher in the MPS III group, but it was not significantly
different from the control group. Although sleep efficiency was
lower in the patient group compared to controls, it did not reach
statistical significance. Daytime sleep duration was significantly
3

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Sleep in MPS III

Table 2. Comparison of MPS III and Control Group Data on the Childrens Sleep Habits Rating Scale.

MPS III

Controls

(n = 8)

(n = 8)

Mean

Median

Mean

Median

(SD)

(IQR)

(SD)

(IQR)

Bedtime resistance

9.5 (2.1)

9.5 (5)

6.3 (0.5)

6.0 (1)

62.0

23.3

0.8

0.001**

Sleep onset delay

2.3 (0.7)

2.0 (1)

1.1 (0.4)

1.0 (0)

57.5

22.9

0.7

0.006**

Subscale

Sleep duration

6.1 (1.6)

6.0 (1)

3.0 (0)

3.0 (0)

60.0

23.3

0.8

0.001**

Sleep anxiety

6.4 (2.7)

5.5 (4)

4.0 (0)

4.0 (0)

56.0

22.9

0.7

0.007**

Night wakings

5.9 (1.5)

6.5 (2)

3.9 (1)

3.5 (2)

55.0

22.5

0.6

0.016*

Night behaviours

3.3 (1.3)

3.0 (2)

2.0 (0)

2.0 (0)

56.0

22.9

0.7

0.007**

Parasomnias

9.8 (1.7)

9.0 (4)

6.4 (0.7)

6.0 (1)

63.0

23.3

0.8

0.000**

Sleep disordered breathing

4.8 (1.8)

4.0 (3)

3.0 (0)

3.0 (0)

56.0

22.9

0.7

0.007**

Daytime sleepiness

16.0 (4.1)

14.5 (8)

12.3 (2.1)

12.5 (2)

51.0

22.0

0.5

0.045*

SD, standard deviation; IQR, interquartile range. Items were grouped into nine subscales. Each item was assigned a score between 1 and 3 and some items were reversescored to ensure that a higher score represented poorer sleep.
*p,.05, **p,.01.
doi:10.1371/journal.pone.0084128.t002

Time 3 on both days (p = 0.016, r = 0.61), but the difference

between Time 1 and Time 3 was just above significance (p = 0.031,
r = 0.59). There were no reliable differences across time points for
the MPS III group on the first day x2(2) = 0.50, p = 0.931, or last
day x2(2) = 2.80, p = 0.367. Visual inspection of the data suggested
that the MPS III group had higher melatonin concentrations at 6
8 h and lower levels at 2224 h, compared to controls, however
Mann-Whitney tests found no significant differences between
groups.

longer in MPS III participants than controls. Group means can be

seen in Figure 1.
In the MPS III group, Spearmans rank correlation coefficients
revealed a positive correlation between age and sleep onset
latency, rs = 0.755, n = 8, p = 0.031, and a negative correlation
between age and sleep efficiency, rs = 20.719, n = 8, p = 0.045. Age
was not significantly correlated with any other variables.

Melatonin Analyses
Melatonin levels by day and time of collection are shown in
Table 5 and the groups are compared in Figure 2. To determine
whether melatonin concentrations were influenced by day of
collection (first day vs. last day), Wilcoxon signed-rank tests were
conducted on patient and control group data, which revealed no
significant effects of day (p.0.05). A Friedman test indicated that
there was a statistically significant difference in melatonin
concentrations for the control group across time points (Time
1:68 h, Time 2:10 h-12 h, Time 3:2224 h) on the first day,
x2(2) = 10.33, p = 0.002, and last day, x2(2) = 9.33, p = 0.006. Post
hoc Wilcoxon tests with Bonferroni correction (adjusted alpha
level of 0.016) showed a significant difference between Time 2 and

Discussion
Children with MPS III took longer to fall asleep and slept more
during the day compared to age-matched typically developing
children, thus supporting the initial hypotheses. There were trends
towards diminished sleep efficiency and increased nocturnal
wakefulness in the patient group. Night-time sleep duration was
not depleted in the patient group which contradicted the
hypothesis. As predicted, responses on the Childrens Sleep Habits
Rating Scale revealed that parents of children with MPS III
reported greater sleep disturbance in all domains, compared to

Table 3. Sleep Parameters (per night) for MPS III Participants Averaged over the Recording Period.

Age (years)
Sleep variable

P1

P2

P3

P4

P5

P6

P7

P8

Control

10

10

11

14

15

mean

Time in bed (min)

570.9

589.5

593.8

579.1

528.8

558.2

659.4

397.4

544.9

Night-time sleep (min)

507.2

504.5

396.6

497.3

464.9

484.0

532.8

190.2

479.0

Daytime sleep (min)

46.5

1.2

40.6

16.4

6.0

1.7

Sleep onset latency (min)

38.6

6.3

24.8

30.4

32.2

39.1

70.9

183.3

14.2

Sleep efficiency (%)

81.0

79.6

59.3

79.2

73.7

77.5

70.5

28.6

80.8

WASO (min)

63.7

85.0

197.2

81.8

63.9

74.2

126.6

207.2

75.1

WASO, wake after sleep onset.

doi:10.1371/journal.pone.0084128.t003

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Sleep in MPS III

Figure 1. Mean actigraphic results of MPS III (n = 8) and control groups (n = 8). Error bars represent standard error of the mean. (A) Duration
of time in bed. (B) Duration of night-time sleep. (C) Duration of daytime sleep. (D) Sleep onset latency. (E) Sleep efficiency. (F) Wake after sleep onset. *
p,0.05, ** p,0.01.
doi:10.1371/journal.pone.0084128.g001

parents of typically developing children. In the patient group,

increased age was associated with greater sleep onset latency and
lower sleep efficiency. As hypothesised, MPS III children showed
disruption in their circadian system.

The MPS III group took an average of 53 minutes to fall asleep

compared to the expected 2030 minutes [24], [25]. The
prolonged sleep onset latency in MPS III suggests difficulties
initiating sleep that could relate to low night-time melatonin levels.
On average, MPS III patients slept during the day for 14 minutes,
with those in the late stage sleeping more during the day than
those in the middle phase. This was in line with previous PSG
findings [12]. It should be noted that daytime sleepiness in
children is associated with behavioural problems, depression, and
reduced quality of life [26]. With increasing age, children with
MPS III took longer to fall asleep and their sleep was less efficient.
Children normally sleep for at least 80% of their time in bed [27],
[28], but the average of the MPS III group was 68.7%. However
sleep efficiency for some children was only just below normal with
only two participants showing very poor sleep efficiency (59.3%
and 28.6% respectively). The length of time that MPS III children
were awake at night was very high, with an average of almost two
hours per night and such wakefulness was particularly noticeable
in the two oldest children.
In Mariotti and colleagues [12] paper night-time sleep was
reduced in MPS III. In the current study average night-time sleep
in the MPS III group was lower than controls, however it was not
significantly different. Some patients sleep varied from one night
to the next, and when sleep was averaged over the recording
period, children with MPS III appeared to be getting a sufficient
quantity of sleep. All Mariotti and colleagues [12] subjects were
MPS IIIA, whereas the current study included both A and B
subtypes. This might account for some of these differences, as
might the disparity in subjects ages across the two studies.
Results from the Childrens Sleep Habits Rating Scale showed
that in comparison to typically developing children, parents of

Table 4. Comparison of Sleep Parameters in Children with

MPS III and Controls.

MPS III

Controls

n=8

n=8

Sleep
parameter

Median
(IQR)

Median
(IQR)

Time in
bed (min)

575.0
(56.6)

531.6
(55.6)

44.0

21.3 0.3 0.23

Night-time
sleep (min)

490.6
(92.9)

496.2
(61.4)

32.0

Daytime
sleep (min)

3.6
(34.6)

0
(0)

48.5

22.0 0.5 0.046*

Sleep onset
latency (min)

35.4
(36.8)

14.9
(7.6)

56.0

22.5 0.6 0.01**

Sleep
efficiency (%)

75.6
(17.4)

82.8
(15.1)

17.5

21.5 0.4 1.4

WASO
(min)

83.4
(113.1)

60.4
(94.7)

43.0

21.2 0.3 0.279

1.0

WASO, wake after sleep onset; SD, standard deviation.

*p,.05, **p,.01.
doi:10.1371/journal.pone.0084128.t004

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Sleep in MPS III

Figure 2. Melatonin concentrations (average 6 SEM) in MPS III patients and controls. Saliva samples were collected at the times shown
on. (A) First day of actigraphic monitoring. (B) Last day of actigraphic recording.
doi:10.1371/journal.pone.0084128.g002

pharmacological intervention, as substantiated by previous

research [11]. The strongest evidence for the efficacy of melatonin
is for reducing sleep onset latency, but there is less support for its
effect on nocturnal waking [31]. Compared to the usual fast
release form, sustained-release melatonin can improve sleep
maintenance in children with neurodevelopmental disorders
[32], but such treatment could exacerbate daytime sleepiness,
which should be avoided in patients who already display tiredness
during the day. Moreover, melatonin should be used with caution
given concerns about its use with children, its long-term effects are
unknown [33] and there is some evidence of an increase in seizures
in children with neurodevelopmental disorders with epilepsy [34].
As with much research into very rare disorders, the current
sample size was small with limited statistical power to detect
between-group differences or disparities between subtypes or
stages of the disorder. Inspection of standard deviations revealed
the MPS group had more variability on all sleep measures
compared with controls, and sleep difficulties, particularly sleep
onset latency and sleep efficiency, worsened as the children aged
and the disease progressed.
With regard to the feasibility of actigraphy with this population,
it is inherently more accurate than diary entries and parents
reported few problems with their child tolerating the watch, which
suggests it is suitable for wider use in both clinical practice and
research with MPS III patients.
Further investigations are needed to validate the findings of this
study. With more resources, a larger sample including adults as
well as children, would substantiate these results and provide
greater clarity of sleep at different stages of the disorder. Some
parents of children with MPS III reported that occasionally their
child would not sleep at all for one night and this unpredictability
makes it difficult to plan their daily lives. Recording over a longer
time period of several weeks, would allow more variability across
nights to be captured. Rather than averaging data across nights,
time series analysis could identify patterns and allow periods of
sleeplessness to be predicted and a longitudinal study following
MPS III patients through the progression of the disorder would
document more precisely how sleep patterns change with age and/
or subtypes.
A number of promising treatments for MPS III which target the
central nervous system are currently being studied, including
enzyme replacement therapy, hematopoietic stem cell transplantation, gene therapy, and substrate reduction therapy [35]. Until a
clinically efficacious treatment for MPS III has been developed, it

children with MPS III saw their child as having more difficulties
with bedtime resistance, falling asleep, sleep duration, sleep
anxiety, night waking, night behaviours, parasomnias, sleep
disordered breathing and daytime sleepiness. The average age of
onset of sleep difficulties was 2 years old, but sleep disordered
breathing (snoring, snorting/gasping and apnea) can be present
from birth in some instances [29], [30], [6].
In a mouse model paper [18], comparable results to this study
were reported. MPS IIIB mice had higher levels of activity during
the resting phase, a reduced resting phase and lower amplitude
rhythm. This could explain napping during the active phase,
night-time waking and nocturnal activity.
Salivary melatonin analyses showed altered circadian rhythm of
melatonin concentration in MPS III with lower melatonin levels at
night and higher levels early morning. However these differences
were not significantly different from controls, partly due to the
small sample size and large variability within the groups.
Melatonin levels were differentiated at specific time points over
day and night in typically developing children. However in MPS
III patients, no reliable differences across time were found. In
Canal and colleagues [18] study, MPS IIIB mice had a lower
sensitivity to light at the behavioural (shorter phase shift after a
light pulse in the dark) and the molecular level (decreased
expression of vasointestinal polypeptide protein in the suprachiasmatic nucleus (SCN)). If comparable processes hold in humans
with MPS III, this could account for the abnormal melatonin
levels observed in the current study.
Given the abnormal melatonin concentrations observed in MPS
III, exogenous melatonin is likely to be the most effective
Table 5. Median (IQR) Melatonin Concentrations across
Groups, Time points and Days.

Melatonin concentrations (pg/mL) by day and time

First day

Last day

Group

68 h

1012 h

2224 h

68 h

MPS III

14 (14.1)

6.6 (8.6)

19 (20.4)

11 (10) 11.1 (10.2)

1012 h

38.2 (40)

Controls 4.3 (10.8)

11.1 (29)

51.5 (87)

7.7 (9)

45.7 (87.7)

9 (27.8)

2224 h

IQR, interquartile range.

doi:10.1371/journal.pone.0084128.t005

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February 2014 | Volume 9 | Issue 2 | e84128

Sleep in MPS III

remains for clinicians to target manifestations of the condition,

including sleep disturbance, to improve the quality of life of
individuals and their families.

Author Contributions
Conceived and designed the experiments: LVM ML SG EC DJH JEW SJ
BB MC. Performed the experiments: LVM ML. Analyzed the data: LVM.
Contributed reagents/materials/analysis tools: DJH JEW SJ BB KLS.
Wrote the paper: LVM. Recruited participants: LVM ML JEW SJ. Data
entry: LVM. Edited the manuscript: DJH JEW BB.

Acknowledgments
We would like to thank the children and parents who gave their time and
effort to this project.

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